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April 5, 2012

New Studies Highlight Setbacks And Advances In Global Malaria Fight

by editor

Emergence of resistance to the drug artemisinin in western Thailand has created a critical point in global efforts to control and eliminate malaria worldwide, according to a new study published in the Lancet, a British Medical Journal, by researchers at the Texas Biomedical Research Institute and their collaborators in Thailand.

A second study, published concurrently in the journal Science by the same research groups, identifies a major region of the malaria parasite genome associated with artemisinin resistance, raising hope that there will soon be effective molecular markers for monitoring the spread of resistance. Both the Lancet and Science studies were funded by the National Institutes of Health and the Wellcome Trust.

Malaria killed 655,000 people — over one per minute -- in 2010. While these numbers are high, malaria deaths have declined by 30 percent over the past decade, largely because of effective control using treatment with combination therapies containing artemisinin, a plant-derived antimalarial drug developed in China.

Patients infected with malaria parasites who respond poorly to treatment have been observed in Cambodia and stimulated a coordinated World Health Organization effort to eliminate the disease in this region. That effort was based on the premise that drug-resistant malaria was confined to Cambodia. Now that effort needs to be reassessed, the Lancet study concludes.

From 2001 until 2010, the Texas Biomed team and their collaborators in Thailand studied 3,202 patients in clinics located in Northwestern Thailand, 500 miles from the Cambodian focus. They observed a dramatic decline in the drug potency over that period. Further, by measuring drug potency in patients infected with genetically identical malaria parasites, they were able to show that the decline in potency results from the spread of resistance genes.

"Spread of drug resistant malaria parasites within Southeast Asia and overspill into sub-Saharan Africa, where most malaria deaths occur, would be a public health disaster resulting in millions of deaths," said Texas Biomed's Standwell Nkhoma, Ph.D., a lead author of the Lancet report. Resistance to other antimalarial drugs, such as chloroquine and fansidar, has previously spread from Southeast Asia to Africa, providing a chilling precedent for such a scenario.

"The problem we have is that treatment with artemisinin-based drugs will promote spread of resistance, but there are no viable alternative treatment options in Southeast Asia," said Nkhoma.

"Our group wanted to understand what genetic changes have occurred in these parasites," said Texas Biomed's Ian Cheeseman, the first author of the companion report in Science "This study narrows the search to a region of the parasite genome containing around 10 genes. We haven't yet found the precise changes involved, but we are getting close."

The researchers first compared genetic variants in the genomes of parasites from Laos, which are sensitive to the drug, with parasites from Cambodia, that show high levels of resistance and those from Thailand, where both resistant and sensitive parasites occur.

"We found 33 genome regions that were very different in parasites from these three countries" said Anderson "When we examined these regions in more detail in a large collection of parasites from Thailand, we found that one small section of malaria parasite genome on chromosome 13 is strongly associated with parasite resistance".

Identification of a molecular marker for resistance will be critical for monitoring the spread of resistance, for determining how resistance occurs, and for understanding the mechanism of action of the drug. The Science study narrows the search for such a marker, and provides an important advance in the race to avert a public health crisis.